scholarly journals The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Marc M Schumacher ◽  
Rania Elsabrouty ◽  
Joachim Seemann ◽  
Youngah Jo ◽  
Russell A DeBose-Boyd
Keyword(s):  
Autosomal Dominant ◽  
Corneal Dystrophy ◽  
Vitamin K2 ◽  
Biosynthetic Enzyme ◽  
Autosomal Dominant Disorder ◽  
Gene Encoding ◽  
Hmg Coa Reductase ◽  
Abnormal Accumulation ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy

Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

scholarly journals Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Youngah Jo ◽  
Jason S Hamilton ◽  
Seonghwan Hwang ◽  
Kristina Garland ◽  
Gennipher A Smith ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Cultured Cells ◽  
Corneal Dystrophy ◽  
Vitamin K2 ◽  
Cholesterol Homeostasis ◽  
Biosynthetic Enzyme ◽  
Hmg Coa Reductase ◽  
Golgi Transport ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy

Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis.

scholarly journals Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

2020 ◽  
Vol 61 (5) ◽  
pp. 746-757
Author(s):  
Dong-Jae Jun ◽  
Marc M. Schumacher ◽  
Seonghwan Hwang ◽  
Lisa N. Kinch ◽  
Nick V. Grishin ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Corneal Dystrophy ◽  
Inhibitory Effect ◽  
Synthetic Activity ◽  
Autosomal Dominant Disorder ◽  
Intact Cells ◽  
Rate Limiting Step ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy ◽  
Rate Limiting

The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.

scholarly journals Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase

PLoS Genetics ◽  
2019 ◽  
Vol 15 (7) ◽  
pp. e1008289 ◽  
Author(s):  
Shi-You Jiang ◽  
Jing-Jie Tang ◽  
Xu Xiao ◽  
Wei Qi ◽  
Suqian Wu ◽  
...  
Keyword(s):  
Corneal Dystrophy ◽  
Cholesterol Accumulation ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy

scholarly journals Author response: Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice

2019 ◽  
Author(s):  
Youngah Jo ◽  
Jason S Hamilton ◽  
Seonghwan Hwang ◽  
Kristina Garland ◽  
Gennipher A Smith ◽  
...  
Keyword(s):  
Corneal Dystrophy ◽  
Author Response ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy

Cloning and Characterization of a Gene Encoding HMG-CoA Reductase fromGanoderma lucidumand Its Functional Identification in Yeast

2008 ◽  
Vol 72 (5) ◽  
pp. 1333-1339 ◽  
Author(s):  
Chang-Hua SHANG ◽  
Fen ZHU ◽  
Na LI ◽  
Xiang OU-YANG ◽  
Liang SHI ◽  
...  
Keyword(s):  
Functional Identification ◽  
Gene Encoding ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Molecular cloning, characterization and function analysis of the gene encoding HMG-CoA reductase from Euphorbia Pekinensis Rupr

2009 ◽  
Vol 37 (3) ◽  
pp. 1559-1567 ◽  
Author(s):  
Xiaoying Cao ◽  
Zhimin Zong ◽  
Xiuyun Ju ◽  
Yong Sun ◽  
Chuanchao Dai ◽  
...  
Keyword(s):  
Molecular Cloning ◽  
Function Analysis ◽  
Gene Encoding ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
And Function ◽  
Euphorbia Pekinensis Rupr

scholarly journals Structural basis for the HMGCR interaction with UBIAD1 mutants causing Schnyder corneal dystrophy

2020 ◽  
Author(s):  
Fengbo Zhou ◽  
Jayne S. Weiss ◽  
Weikai Li
Keyword(s):  
Md Simulation ◽  
Autosomal Dominant ◽  
Corneal Dystrophy ◽  
Structural Basis ◽  
Structural Flexibility ◽  
Transmembrane Helices ◽  
Concentration Increase ◽  
Dominant Disease ◽  
Schnyder Corneal Dystrophy ◽  
Homology Models

AbstractSchnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by abnormal deposition of cholesterol and lipid in the cornea. The molecular mechanism underlying this process, which involves the interaction between UBAID1 and HMGCR, remains unclear. Here we investigate these events with in silico approaches. We built the homology models of UBIAD1 and HMGCR based on the existing crystal and cryo-EM structures. The UBIAD1 and HMGCR models are docked and their binding interactions are interrogated by MD simulation. We find that the transmembrane helices of UBIAD1 bind to sterol sensing domain of HMGCR. Upon binding of the GGPP substrate, UBIAD1 shows lower structural flexibility in the TM regions binding to HMGCR. The N102S and G177R mutations disrupts GGPP binding, thereby lowering the binding affinity of HMGCR. Overall, our modeling suggests that SCD mutations in UBIAD1 or lower GGPP concentration increase the structural flexibility of UBIAD1, thereby facilitating its association with HMGCR.

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